PROJECT SUMMARY The objective of the current proposal is to determine when and how infants' stress responsivity is calibrated by maternal depression, and how this calibration translates into child emotional and behavioral problems. Psychological health relies on the regulation of stress-responsive physiological systems?i.e., hypothalamic- pituitary-adrenal (HPA) axis, autonomic nervous system (ANS), and inflammatory mediator (IM) responses that match the demands of a given stressor and recover promptly once it has passed. It is important to clarify how these systems become dysregulated in order to identify and intervene on risk trajectories. Previous cross- sectional research highlights maternal predictors and child outcomes related to dysregulation of one or more of these systems but fails to address the possibility that within-person development of stress responsivity across systems offers a critical window into early risk. We will test the central hypothesis that early exposure to maternal depression predicts sensitization of HPA, ANS, and/or IM function that undermines the child's psychological health through the following specific aims: (1) Determine whether maternal depression induces upward calibration of infant stress responsivity across systems; (2) Identify maternal depression profiles with the strongest impact on infant stress calibration; and (3) [Characterize maladaptive stress system development through associations between infant stress response trajectories and deficits in self-regulatory functions.] A community sample of [250 expectant mothers?over half with a diagnosed major depressive episode and the rest with no diagnoses]?will be recruited during pregnancy and followed through the first 2 postnatal years. At 3, 8, 15, and 24 months the infant will be exposed to developmentally appropriate interpersonal stressors to assess stress responsivity, with salivary cortisol tapping HPA, alpha-amylase (sAA) tapping ANS, and a composite of IL-1b, IL-6, TNF-a, and CRP tapping IM activation. Child self-regulatory development will be assessed via both mother-report and behavioral measures at 24 months. We hypothesize that mothers' depression symptoms will predict child stress sensitization from 3-24 months, evidenced by a trajectory of increasing/nonrecovering multi-system activation over time. The strongest effects are expected for early (prenatal, 3-month postnatal) depression symptoms in mothers who have crossed a diagnostic threshold for a lifetime depressive disorder. We further expect child stress sensitization?[especially high/increasing concordant activation across HPA and IM, but low/decreasing concordance across HPA and ANS]?will predict poorer executive function and emotion regulation at 24 months. Achieving these aims will clarify how stress-responsive systems are calibrated by maternal depression and how this calibration confers risk for later disorder. The findings will inform a truly developmental model of stress-related dysregulation while defining novel stress physiology targets for early mother/infant intervention to mitigate psychological health risks in children of depressed mothers.